Respiratory epithelial-cell surfaces present a large interface with the external environment and provide the first line of defense against a broad array of microbes. Initially perceived as a passive barrier between the host and the environment, the lung is now known to constitute a robust system of immune surveillance that include epithelial cells as well as highly specialized professional antigen presenting cells (APC) distributed throughout the conducting airways and the lung parenchyma. However, the critical elements required for development of protective immunity and the maintenance of immune homeostasis in the lung are largely unknown, particularly in the steady state in the human. This is important because uncontrolled or skewed immunity in the lung might lead to illness as for example might be the case in the link between RSV infection in childhood and increased susceptibility to asthma in adult life. Dendritic cells (DC) play a pivotal role in initiating the immune response to foreign antigens and in the maintenance of tolerance to self antigens. Drs Merad and Palucka laboratories have been working on the mechanisms that control the development and function of DC for more than ten years. Recent data from our groups revealed that the DC networks in nonlymphoid tissues consist of developmentally distinct and functionally specialized DC subsets in mice and humans. In this application, we propose to establish the functional specialization of the DC network in the lung and identify the mechanisms that control DC functional specialization in the induction of mucosal antiviral immunity. We will do so by studying mouse DC in vivo, human DC in humanized mice models as well as human lung. In our preliminary studies we have used influenza virus to probe the function of DC subsets in the lung. GFP-expressing virus differently interacts with distinct DC subsets. We show that distinct DC subsets preferentially interact with CD4+ or CD8+ T cells. These results support our hypothesis that the lung DC network consists of different subsets that differently control the induction of cellular and humoral immunity to respiratory viruses. Research proposed will be carried out through a collaborative effort between three established investigators with distinct and complementary expertise uniquely suited to address the central hypothesis of this application. The PI of this application, Dr. Miriam Merad (Mount Sinai School of Medicine (MSSM)) is an expert in mouse DC biology and has made several key contributions to our understanding of mucosal DC development and function in mice. Dr. Karolina Palucka (Joint investigator at Baylor Institute for Immunology Research (BUR) and MSSM) is a world expert in human DC biology and in humanized mouse models. Dr. Adolfo Garcia Sastre (MSSM) is a virologist and a world expert in influenza virus. In addition, Dr. Christian Becker (a pulmonologist at MSSM and a member of Merad's laboratory) has developed a strong human lung explants program with access to more than 100 fresh human lung samples per year. PUBLIC HEALTH RELEVANCE: The critical elements required for development of protective immunity and the maintenance of immune homeostasis in the lung are largely unknown, particularly in the steady state in the human. Here we propose to use mouse models of lung viral infections, humanized mice models and human lung explants to examine the role of dendritic cells subsets in the modulation of mucosal immune defense mechanisms.